Smoking remains the number one avoidable cause of death in the United States and costs the economy tens of billions of dollars every year. Current therapies include nicotine replacement with a patch or gum, inhibition of the dopamine system with bupropion, and partial activation of the ?4?2 neuronal nicotinic acetylcholine receptor (nAChR) with varenicline. None of these have been particularly effective upon initial use, and even in the cases of initial success relapse rates are nearly 80% regardless of the treatment drugs or therapies. Additional therapies in clinical trials include the non-selective nAChR antagonist mecamylamine, nicotine antibodies, and behavior modification. The nAChR most closely associated with the addictive nature of cigarettes is the ?4?2 nAChR. Activation of thi receptor is considered to be the primary mediator of nicotine reward and the selective but low affinity ?4?2 nAChR antagonist DH?E has been demonstrated to block nicotine self-administration in rodent models. However, there are very few high affinity and selective ?4?2 antagonists available to examine as smoking cessation medications. Starting from a small molecule combinatorial library containing more than 5 million individual compounds, we have identified selective nAChR compounds. With funding from our Phase I application we have identified lead compounds with very high affinity, potency and selectivity, both with respect to binding affinity and in vitro functional activity, at the ?4?2 nAChR. Both of these compounds ae full antagonists at ?4?2 nAChRs. One compound has been demonstrated to attenuate nicotine self-administration and reinstatement in rats. In this Phase II SBIR, we propose to optimize our lead compounds to further improve drug-like properties, while maintaining or improving affinity and selectivity. In Specific Aim 1, similar to a traditional drug discovery hit-to-lead process, additional SAR will be conducted to improve the PK/PD properties of our current lead compounds. This aim will include medicinal chemistry and coupled with in vitro affinity and efficacy testing along with the pharmacological profiling to identify drug-like compounds. Specific Aim 2 will be similar to the lead to development process within drug discovery, in which selected high affinity and selective antagonists will be tested in a battery of in vitro and n vivo assays to determine oral bioavailability, stability, blood brain barrier penetration, pharmacokinetics, and hERG inhibition. In addition to determining in vivo efficacy for ability to block nicotine self-administration and reinstatement in rats, this aim will include the determination of additional pharmacological effects on locomotion, anxiety, depression, and reward/aversion, in order to choose compounds to move forward to future IND-enabling toxicology.